1.1. Cyclopropanation Strategies in Recent Total Syntheses1

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Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

1.2. 1. Cyclopropanation Methods

1.1 Simmons–Smith Cyclopropanation In 1958, H. E. Simmons and R. D. Smith at DuPont reported the formal cycloaddition of methylene and various olefins by treatment of diiodomethane with zinc-copper couple Zn(Cu).2 The synthetic utility of this method derives mainly from the large scope of olefins that can be employed as substrates as well as stereospecificity of the transformation,3 so that the stereochemical information of the olefin is transferred to the product. A strong directing-effect may be observed, when the substrate bears Lewis basic heteroatoms in proximity to the olefin.4 A representative, simple example is shown in Scheme 1, in

which cyclohexene-1-ol (1) is exposed to CH2I2 and Zn(Cu) providing 2 as a single diastereomer in 63% yield.

Scheme 1: Simmons–Smith cyclopropanation of cyclohexene-1-ol (1).

In 1959, Wittig and Schwarzenbach reported that exposure of diazomethane to zinc iodide in ether 5 provided IZnCH2I. Furthermore, Furukawa et al. developed a method that has been widely adopted for 6 the generation of the zinc carbenoid in which diiodomethane is treated with ZnEt2. The carbenoid species generated under the Furukawa conditions displays high reactivity with electron-rich olefins such as styrenes, enol ethers and enamines as well as for substrates containing Lewis basic directing groups. In 1991, Denmark and Edwards showcased the superior cyclopropanation properties of a carbenoid 7 generated from ZnEt2 and ClCH2I. Shi and co-workers have noted that the zinc carbenoid can be rendered more reactive by ligand exchange process.8 In their landmark study, one equivalent of Brønsted acids, such as alcohols, amines,

carboxylic or sulfonic acids, was added to equimolar amounts of ZnEt2 followed by one equivalent of CH2I2. The electron-withdrawing effect of trifluoroacetic acetate as a ligand on zinc is suggested to trigger a dramatic increase in the reaction rate. To date, the generated (F3CCO2)ZnCH2I carbenoid represents one of the most reactive reagents for cyclopropanation. Moreover, Charette and co-workers reported phosphoric acid-derived zinc carbenoids also display enhanced reactivity.9

1.2 Diazo-Derived Carbenoids The discovery that metal salts catalyze the decomposition of diazo compounds dates back to 1906, when Silberrad and Roy investigated the effect of copper dust on ethyl diazoacetate.10 A milestone was reached in the 1960’s, when catalytic homogeneous diazo decomposition was enabled by soluble copper 11 complexes. A decade later, Teyssie discovered that Pd(OAc)2 and Rh2(OAc)4 are suitable alternatives to copper salts.12

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 2. Diazo-derived carbenoids for the cyclopropanation of olefins.

Several important aspects need to be taken into account when consideration is given to the use of a diazo-derived carbenoid for a cyclopropanation reaction in the synthesis of complex molecules (Scheme 2). Firstly, because alkyldiazo compounds lacking stabilizing groups are considered capricious, they are typically generated in situ.13 Secondly, in case of intermolecular cyclopropanation (3 → 4) slow addition of the diazo compound to a mixture of the olefin and a metal catalyst may be necessary in order to avoid carbene dimerization.14 Thirdly, chemoselective discrimination between cyclopropanation and C–H insertion pathways can be an important issue. In this respect, elegant studes by Padwa and Doyle showcase that chemoselectivity can be significantly influenced by the nature of the catalyst employed.15 Even for diazoketone 7, possessing both, a γ,δ-olefin and a γ-methine C–H, complete selectivity can be achieved. As shown in Scheme 3, while Rh2(OAc)4 produces a 1:1 mixture of 8 and 9, Rh2(pfb)4 furnishes solely the product of C–H insertion. In contrast, the use of Rh2(cap)4 produced only cyclopropane 8.

Scheme 3. Chemoselectivity study between C–H insertion and cyclopropanation by Padwa and Doyle.

The intramolecular variant of this transformation (cf. Scheme 2, 6 → 5) has gained considerable popularity in natural product synthesis, as two rings can be stereoselectively generated in a single step and, depending on the olefin employed, highly substituted cyclopropanes can be accessed.16

1.3 Free Carbenes As early as 1862, Geuther discovered that chloroform undergoes decomposition in alkaline alcohol solutions.17 Almost 100 years later, Doering and Hoffmann treated a mixture of cyclohexene and a

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses solution of KOt-Bu in t-BuOH with chloroform and observed a vigorously exothermic reaction (Scheme 4).18 The product formed was identified as 7,7-dichlorobicyclo[4.1.0]heptane (17) and its formation was attributed to the generation of dichlorocarbene (15) via base-mediated α-elimination. Several years later, Cory and McLaren showcased the enormous potential of this method during their total synthesis of ishwarane (21).19 Olefin 18 was treated with tetrabromomethane and an excess of methyl lithium at −78 °C, mediating the formation of dibromocyclopropane 19. Upon warming of the reaction mixture to –30 °C, lithium-halogen exchange and subsequent α-elimination occurred, generating cyclopropylcarbene 20, which participated in a C–H insertion reaction to yield ishwarane (21).

Scheme 4. Formation of dichlorocarbene and total synthesis of ishwarane by Cory and McLaren.

In 1967, Crandall and Lin discovered that α-lithiated epoxides are prone to undergo elimination, leading to carbene formation.20 When epoxide 22 was exposed to t-BuLi, cyclopropanol 23 was isolated as a minor product in 9% yield (Scheme 5). Intriguingly, the anti-isomer was the only observed product, a finding attributed cycloaddition proceeding through chair-like transition state 24.21

Scheme 5. α-Lithiation and elimination of epoxides.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

During their investigation of the α-deprotonation of epoxides, Mioskowski and co-workers discovered that epoxide 25 furnished cyclopropane 26 via carbene 27, albeit in low yield.22 In the early 2000’s, Hodgson became interested in optimizing this intriguing transformation in light of the fact that enantioenriched epoxides are widely available via Jacobsen hydrolytic kinetic resolution.23,24 After a laborious screening, Hodgson and co-workers found that high yields (60-84%) can be obtained by slow addition of LiTMP to a solution of the epoxide substrate at 0 °C, followed by warming to ambient temperature. This method provides the anti-product isomer, a stereochemical outcome that is complementary to that observed in the Simmons–Smith cyclopropanation reaction, which otherwise leads to cis-isomer 28 as a consequence of known directing effects in the reaction of allylic alcohols.

1.4 Cycloisomerization In 1976, Ohloff and co-workers reported a seminal observation in which propargylic acetate 29 was 25 converted to 30 in 70% yield upon exposure to ZnCl2 (Scheme 6). Intriguingly, cyclopropane 31 was formed as a side product in minor amounts (5%). Some years later, Rautenstrauch described a novel approach for the synthesis of cyclopentenones, a transformation which is referred to as the Rautenstrauch rearrangement.26 When enyne 32 was exposed to a Pd(II) catalyst, cyclopentenone 33 was isolated in 50-61% yield. Rautenstrauch proposed a mechanism in which the alkyne undergoes acetoxy palladation to give intermediate 34. Subsequent displacement of the acetoxonium by the vinyl-palladium species furnishes a putative palladacycle (35) that is suggested to undergo reductive elimination and hydrolyze to form 33.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 6. Cycloisomerization of propargylic acetates by Ohloff and Rautenstrauch.

A pivotal discovery was made by Fensterbank and Malacria when dienyne 36 was exposed to PtCl2 at elevated temperatures (Scheme 7).27 The free alcohol substrate as well as the corresponding methyl and silyl ethers provided 38, while the acetate derivatives gave 37. The authors suggested that in the absence of an acetate, zwitterion 41 cyclizes to cyclopropane 42. The generated intermediate platinum carbene then participates in a second intramolecular cyclopropanation reaction to yield 38. For the acetylated substrate, an acetoxonium organoplatinum intermediate is formed (39) analogous to 34 which leads to metallocarbene that subsequently is engaged in an intramolecular cyclopropanation to afford 37. Building on these discoveries, Toste reported a remerkable gold(I)-catalyzed Rautenstrauch rearrangement, generating cyclopentenones from propargylic pivalates in high yields.28 Additionally, Fürstner and co-workers reported a versatile gold- and platinum-catalyzed method for the synthesis of cyclopropane substituted cyclopentanones from propargylic acetates.29

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 7. Pt-catalyzed cycloisomerization of enynes and the effect of oxygen substitution.

A conceptually different cycloisomerization was reported by Trauner and Miller in 2003, inspired by biosynthetic considerations (Scheme 8).30 The focus of the studies by Trauner was the synthesis of polyketides featuring a bicyclo[3.1.0]hexane core, such as photodeoxytridachione (43), tridachiapyrone (44) and crispatene (45). In order to establish efficient entry into this natural product class, a novel Lewis acid-catalyzed cyclization reaction of hexatrienes was developed. Trauner and Miller discovered that catalytic amounts of Me2AlCl mediated a [π4a+π2a] cycloaddition to give cyclopropane 47 in 73% yield.

Scheme 8. Polypropionate natural products and Lewis acid-catalyzed cycloisomerization by Trauner and Miller.

1.5 Kulinkovich Reaction In 1989, Kulinkovich reported one of the most intriguing reaction in modern organotitanium- chemistry. Treatment of aliphatic esters with ethylmagnesium bromide in the presence of Ti(OiPr)4 generated 1-alkylcyclopropanols such as 49 (Scheme 9).31,32 The mechanism of this unusual cyclopropanation has been intensively investigated using deuterium labeling studies by Kulinkovich and computationally by Wu and Yu,33,34,35 leading to the conclusion that the reaction proceeds through a titanacyclopropane, or Ti(II)-olefin, intermediate. Importantly, Kulinkovich and co-workers could demonstrate that exchange of ethylene with substituted olefins was possible, thus enabling the generation of more substituted cyclopropanols (cf. 48 → 50).36

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 9. The Kulinkovich reaction.

Two modifications have been developed by de Meijere and Szymoniak, in which amides and nitriles serve as starting materials culminating in the generation of aminocyclopropanes (Scheme 10).37,38

Scheme 10. Modifications of the Kulinkovich reaction.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

1.6 Nucleophilic Displacement Reactions In 1884, W. H. Perkin reported the cyclopropanation of diethyl malonate with 1,2-dibromoethylene in the presence of NaOEt (Scheme 11).39 In numerous studies, stabilized carbanions have been shown to undergo analogous double alkylation to furnish cyclopropanes.40 Pirrung and co-workers discovered that cyclopropanated γ-lactones are formed when malonates are treated with epichlorohydrin and base.41 A groundbreaking method was introduced by Corey, who discovered that enones react with dimethylsulfoxonium methylide to form cyclopropanes, a process known as the Corey–Chaykovsky reaction.42

Scheme 11. Nucleophilic cyclopropanations.

A landmark in the synthesis of cyclopropane containing natural products was reported by Büchi in 1966.43 During the total synthesis of aromadendrene, aldehyde 62 underwent addition of HBr and subsequent exposure of the crude bromide to KOt-Bu provided cyclopropane 63 in 41% overall yield. Another remarkable cyclopropanation reaction was employed by Danishefsky and Chu-Moyer during their total synthesis of the diterpene myrocin C (67, Scheme 12).44 When diene 64 was treated with (trimethylstannyl)lithium, cyclopropane 66 was isolated in 66% yield.

Scheme 12. Nucleophilic cyclopropanation by Danishefsky and Chu-Moyer during the total synthesis of myrocin C.

In 2009, Lambert reported a conceptually different approach for the generation of a cyclopropane, relying on the Lewis acid-mediated nucleophilic attack of olefins onto epoxides.45 As shown in Scheme

13, treatment of epoxide 68 with 5 mol% La(OTf)3 at 40 °C provided cyclopropane 69 in 72% yield. The mechanism as proposed by the authors describes initial attack of the olefin onto the activated epoxide, followed by a semi-pinacol rearrangement to produce the cyclopropyl product. Notable advantages of this method are the high stereospecificity and the broad substrate scope. H

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 13. La(OTf)3-catalyzed cyclopropanation of epoxyolefins by Lambert.

2.0 Recent Application in Total Synthesis

2.1 Applications of Simmons Smith

2.1.1 Lundurine by Qin. (–)-Lundurine A (72) is an indoline alkaloid, isolated in 1995 from Malaysian Kopsia tenuis (Scheme 14).46 The structure of this natural product is characterized by a tricyclic core, incorporating a

Scheme 14. Qin’s total synthesis of (–)-lundurine A via an intramolecular Simmons–Smith cyclopropanation.

densely substituted cyclopropane as well as four stereocenters. Qin and co-workers concluded that a late stage intramolecular Simmons–Smith cyclopropanation reaction of 73 involving the indole and a

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses carbenoid would simultaneously solve the problem of installation of the challenging cyclopropane as well as the tricyclic core of the natural product. The key advanced azocane intermediate was formed via intramolecular nucleophilic displacement of the primary iodide in 74, available in four steps from a known substituted indole.47 Subsequent addition of allylMgBr furnished amine 75, which was further converted into aldehyde 76 in three additional steps. Barton’s protocol was employed in order to convert the aldehyde into gem-diiodide 77,48 setting the stage for an intramolecular Simmons–Smith cyclopropanation reaction. Hence, treatment of 77 with an excess of ZnEt2 furnished cyclopropane 78 in 63% yield from aldehyde 76. After deprotection and dehydration, (–)-lundurine A (72) was obtained.

2.1.2 Kalesse’s synthesis of (+)-omphadiol

Scheme 15. Total synthesis of (+)-omphadiol by Kalesse and co-workers.

The sesquiterpene (+)-omphadiol (79) was isolated in 2000 from the fungi Omphalotus illudens (Scheme 15).49 This natural product contains a 5–7–3 ring system and six contiguous stereocenters. In addition to the synthesis of the trans-fused cyclopentane moiety, the stereoselective introduction of the cyclopropane represents a challenge. Noteworthy, the potential directing effect of the C(5) alcohol, which might lead to the undesired stereoisomer, must be taken into account while planning the synthesis route. Recently, Kalesse and co-workers described an approach that allows for a stereoselective generation of the trans cyclopentane. Bicyclic enone (–)-81 was subjected to conjugate addition followed by aldol condensation with 83 to give 84. This sequence exploited the shielding effect of the norbornene to ensure that enone functionalization takes place from the concave face. Flash vacuum

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses pyrolysis of advanced intermediate 85 then provided highly substituted cyclopentane 86 in 75% yield. Interestingly, upon exposure of olefin 87 to Simmons–Smith conditions the free alcohol at C(5) did not exert any directing effect providing (+)-omphadiol (79) in 12 steps from ketone (–)-81. This may result from the steric hindrance associated with the neopentyl-like alcohol or alternatively suboptimal disposition between alcohol and olefin of the cycloheptenyl ring to enable directed methenylation.

2.1.3 Carreira’s synthesis of pallambins A and B The norditerpenoids pallambins A (88) and B (89), isolated in 2012 from extracts of the liverwort Pallavicinia ambigua, possess a hexacyclic scaffold equipped with ten contiguous stereocenters, out of which two are quaternary (Scheme 16). A formidable challenge in any total synthesis endeavor arises from the tetracyclo[4.4.03,5.02,8]decane core comprising an encumbered cyclopropane that includes double gauche pentane like interactions with the C(10) methyl group. In their total synthesis of pallambins A and B, Carreira and Ebner planned for the introduction of the cyclopropane prior to the installation of the C(10) methyl group.50 Accordingly, chemo- and diastereoselective Simmons–Smith

Scheme 16. Total synthesis of pallambins A and B by Carreira and Ebner.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses cyclopropanation of diene 91 followed by diastereoselective hydrogenation of the remaining exo-olefin was envisioned. Diene 91 was prepared from an unprecedented Diels–Alder reaction between pentafulvene (93) and methyl acrylate. While various cyclopropanation protocols either showed lack of reactivity or chemoselectivity (endo- vs. exo-olefin), exposure of 91 to Denmark’s conditions7 provided cyclopropane 90 in 85% yield as a single diastereomer. Subsequent reduction of the remaining olefin with Wilkinson’s catalyst furnished ester 94 in 96% yield (d.r. > 20:1). The tetracyclic core of the natural products was completed by diazo transfer and C–H insertion of 95 giving diketone 97 in 76% overall yield. Palladium-catalyzed alkoxycarbonylation under the conditions described by Yang and co-workers followed by aldol condensation then yielded pallambins A (88) and B (89).51

2.1.4 Maimone’s synthesis of (–)-6-epi-ophiobolin N The discovery of the ever expanding ophiobolin class of natural products commenced in 1958 with the isolation of ophiobolin A.52 These sesterterpenes possess a characteristic fused 5–8–5 ring system, representing an exceptional challenge for total synthesis. In 2016, Maimone and co-workers documented a concise approach towards the recently isolated 6-epi-ophiobolin N (100),53 relying on an anionic cyclopropane fragmentation of iodide 102 (Scheme 17).54

Scheme 17. Total synthesis of (–)-6-epi-ophiobolin N by Maimone and co-workers.

The use of a halogenated cyclopropane as a synthon for a homoallylic organometal species is a strategic coup that allows straightforward asymmetric access to a key intermediate. Furthermore, the tricyclic skeleton of the targeted natural product was envisioned to be generated from a radical-mediated cyclization cascade of trichloride 101. Farnesol (104) was subjected to Charette’s enantioselective Simmons–Smith cyclopropanation conditions,55 followed by Appel reaction to furnish cyclopropane 102 in 58% yield. Subsequent lithium- halogen exchange triggered anionic cyclopropane opening. After transmetallation with CuI·SMe2, enone L

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

103 was added, followed by trichloroacetyl chloride, providing 101 in 60% yield. Following ketone reduction and alcohol protection, a remarkable radical cascade, initiated by BEt3, generated the 5–8–5 ring system. Four steps later, 6-epi-ophiobolin N (100) was obtained.

2.2 Diazo-Derived Carbenoids

2.2.1 Liu’s synthesis of (–)-bolivianine The sesterterpenoid (–)-bolivianine (109), isolated in 2007 from the Chloranthaceae Hedyosmum angustifolium, possesses a highly congested seven-membered ring system, including a cyclopropane unit.56

Scheme 18. Total synthesis of (–)-bolivianine by Liu and co-workers.

In their synthesis of this complex natural product, Liu and co-workers introduced the cyclopropane through the use of allylic carbenoid 112 (Scheme 18).57 Additionally, a biomimetic Diels–Alder/hetero- Diels–Alder cascade between aldehyde 111 and β-E-ocimene (110) was planned to rapidly generate (–)- bolivianine (109). Aldehyde 113, available in only four steps from (+)-verbenone, was transformed into tosylhydrazone

114 in 83% yield. Upon exposure to sodium methoxide and Pd2(dba)3 carbenoid 115 was formed in situ, which selectively gave cyclopropane 116 in 65% yield. After seven additional steps, aldehyde 111 was obtained, which underwent the desired Diels–Alder/hetero-Diels–Alder cascade with 110 to give (–)- bolivianine in impressive 55% yield. M

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

2.2.2 Reisman’s synthesis of (+)-salvileucalin B (+)-Salvileucalin B (117) was isolated in 2008 from the aerial parts of Salvia leucantha, an evergreen herbaceous plant, by Takeya and co-workers.58 This cytotoxic natural product is structurally characterized by a central norcaradiene subunit, which is part of a tricyclo[3.2.1.02,7]octane. Strategically, retrosynthetic scission of the central cyclopropane as shown in Scheme 19 would be highly efficient, because it would generate the complex tricyclic core of the natural product in a single step. In 2011, Reisman and co-workers reported the first enantioselective synthesis of (+)-salvileucalin B, relying on such a strategy.59 Importantly, such a disconnection requires the cyclopropanation of an arene, a process initially discovered by Büchner and Curtius,60 which engenders several challenges. Firstly, diazo ketone 119 possesses an activated benzylic methylene group, which could potentially undergo competing C–H insertion to form a cyclopentane. Secondly, the norcaradiene must be formed under conditions which it is precluded from undergoing electrocyclic ring opening to generate the corresponding heptatriene. The central chemoselectivity issue, vis a vis cyclopropanation and C–H insertion had been previously examined by Mander and co-workers in an elegant total synthesis of 61,62 gibberellin GA103. In these studies, the authors discovered that both the nature of the metal catalyst as well as the arene substitution pattern influences the reaction outcome. While dimeric rhodium catalysts produced mixtures of C–H inserted products and norcaradienes, copper catalysts favored cyclopropanation.63 For the total synthesis of (+)-salvileucalin B, an electron-withdrawing group adjacent to the ketone in 118 was required in order to form the γ-lactone. Reisman and co-workers discovered that the nature of this additional functional group has a significant impact on the chemoselectivity of the reaction. While α-diazo-β-ketoesters favor C–H insertion, the corresponding nitriles furnish the norcaradiene products in good yields.64

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 19. Reisman’s total synthesis of (+)-salvileucalin B via an intramolecular arene cyclopropanation.

The central arene unit was generated via a ruthenium-catalyzed cycloisomerization of diyne 120, available in seven steps from propargyl alcohol. Following auxiliary removal and introduction of the α- diazo-β-ketonitrile, 119 was exposed to Cu(hfacac)2 under microwave irradiation to generate norcaradiene 122 in 65% yield. This product could then be converted to (+)-salvileucalin B in five additional steps.

2.2.3 Fox’ synthesis of piperarborenine B In 2013, Fox reported an ingenious enantioselective bicyclopropanation/homoconjugate addition for the generation of tetrasubstituted cyclobutanes (Scheme 20, top).65 α-Cinnamyl-α-diazoesters were observed to form dicyclopropane intermediates, such as 125 that could subsequently undergo homoconjugate opening with an added organometal species to form cyclobutylenolate 126. The latter could be quenched by a collection of electrophiles.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 20. Total synthesis of piperarborenine B by Fox and co-workers.

The utility of this method was showcased by Fox and co-workers in an elegant total synthesis of the cyclobutane-containing natural product piperarborenine B (123).66 After diazoester 128, available in three steps from veratraldehyde, was exposed to their established conditions, only moderate enantioselectivity was achieved. Thus a new dimeric rhodium catalyst was developed (129), which provided cyclobutane 131 in 69% yield and 92% ee after nucleophilic dicyclopropane opening and BHT-mediated proton quench. This bulky proton source was necessary in order to enable diastereoselective protonation of the corresponding enolate. In accordance to Baran’s work the remaining aryl substituent was introduced by C–H activation approaches.67

2.3 Free Carbenes by α-Elimination 2.3.1 Ding’s synthesis of steenkrotin A Steenkrotin A (135), a diterpenoid isolated in 2008 by Hussein and co-workers, contains a fused pentacyclic system as well as eight stereocenters (Scheme 21).68 The stereoselective introduction of the dimethylcyclopropane is an important aspect to consider in planning a synthesis of 135. Consequently, Ding and co-workers envisioned reacting dimethylcarbene (138), generated in situ, with cyclic enol ether derivative 139.69 Importantly, the increased nucleophilicity of the enol ether was expected to lead

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses to its chemoselective functionalization in the presence of the remaining two olefins in 139. A carbonyl- ene reaction was planned in order to generate the tetrahydrofuran.

Scheme 21. Total synthesis of steenkrotin A by Ding and co-workers.

Enone 140 was transformed into the corresponding trimethylsilyl enol ether 142 and then directly treated with dimethylcarbene (138), generated in situ from 141 and n-BuLi. The formation of cyclopropane 143 in 70% yield as a single diastereomer may be explained by the conformation shown in 142. In five steps, aldehyde 144 was synthesized, which upon exposure to HF·pyridine underwent concomitant desilylation and carbonyl-ene reaction to furnish tricycle 145 in excellent 90% yield.

2.3.2 Fukuyama’s synthesis of (+)-lyconadin A

Free carbenes derived from base-mediated α-elimination of HX from CHX3 (X = halogen) have found widespread application for the one carbon ring expansion to generate cyclic vinyl halides.70 In 2011, Fukuyama and co-workers reported the total synthesis of the alkaloid (+)-lyconadin A (146), isolated in 2001 from Lycopodium complanatum,71 in which the tetracyclic core was generated from a dibromocyclopropane intermediate (Scheme 22). 72

Scheme 22. Total Synthesis of (+)-lyconadin A by Fukuyama and co-workers.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Upon exposure of olefin 149 to aqueous formaldehyde under acidic conditions, aza-Prins cyclization occurred, providing tricyclic amine 150 in 94% yield. The cyclopropanation of benzyl-protected 150 proceeded in only 9% yield, a finding which was attributed to an undesired side reaction involving the amine and the in situ generated free carbene. Accordingly, the less nucleophilic Boc-protected amine derivative 151 was prepared. In this case, the desired dibromocyclopropane was isolated in 65% yield upon treatment with bromoform and NaOH under phase transfer conditions. After deprotection, the corresponding secondary amine was refluxed in pyridine, which resulted in cyclopropane opening to cationic intermediate 153. Subsequent intramolecular trapping of the latter by the amine then generated tetracycle 147 in excellent overall yield of 96%.

2.3.3 Yang’s synthesis of (+)-propindilactone G and (+)-schindilactone A Another conceptually related strategy for the one carbon expansion of cyclic systems is the cyclopropanation of cyclic silyl enol ethers with bromoform and a suitable base. The corresponding dibromocyclopropanes are then treated with a silver(I) salt to ultimately generate α-bromoenones. Yang and co-workers employed this procedure during their total syntheses of the nortriperpenoids (+)- propindilactone G (154) and (±)-schindilactone A (155) (

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 23).73,74 Accordingly, silyl enol ether 158 is treated with in situ generated dibromocarbene forming cyclopropane 159. AgClO4 is then used to open the latter to the corresponding α-bromoenone 156.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses

Scheme 23. Total syntheses of (+)-propindilactone G and (+)-schindilactone A by Yang and co-workers.

2.3.4 Hodgson’s synthesis of (–)-cubebol (–)-Cubebol (160) represents one of the major constitutes of cubeb oil, obtained from the berries of Piper cubeba, which is found in Indonesia.75 Except for two recent syntheses by Fürstner and Fehr,76,77 all previous routes have highlighted an α-diazoketone to generate the internal cyclopropane (Scheme 24).78,79,80,81 However, these approaches suffer from moderate yields for the cyclopropanation reaction as well as low diastereoselectivities. In 2009, Hodgson et al. reported a novel synthesis of (–)-

Scheme 24. Synthesis of (–)-cubebol by Hodgson and co-workers.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses cubebol (160) starting from (–)-menthone (164), which was converted into chlorohydrin 165 in four steps.82 Exposure of the latter to n-BuLi and TMP-mediated epoxide formation as well as α-deprotonation with subsequent elimination. The carbene formed then underwent clean cyclopropanation to provide alcohol 166 in 71% yield as a single diastereomer.

2.3.5 Liu’s synthesis of chloranthalactone A A conceptually similar strategy was employed by Liu and co-workers during their total synthesis of the sesquiterpenoid chloranthalactone A (167, Scheme 25).83 Hodgson’s cyclopropanation method using epoxide 169 was envisioned. Ketone 170 was first converted into epoxide 171 in 78% yield, before α- lithiation and elimination was affected by treatment of the latter with LiTMP. The desired cyclopropanated product 172 could thus be isolated in impressive 90% yield. Corey–Winter olefination then provided the required exo-alkene 174, which was converted into chloranthalactone A (167) in three additional steps.

Scheme 25. Total synthesis of chloranthalactone A by Liu and co-workers.

2.4 Cycloisomerizations 2.4.1 Vanderwal’s synthesis of echinopine B The sesquiterpenoid echinopine B (175), isolated in 2008 together with the corresponding carboxylic acid (echinopine A, 182), possesses a unique fused tetracyclic carbon skeleton (Scheme 26).84 While U

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses previous approaches to these intriguing natural products introduce the cyclopropane moiety by either Simmons–Smith cyclopropanation85,86 or intramolecular carbenoid cyclopropanation,87 Vanderwal and co-workers employed a Pt-catalyzed cycloisomerization reaction (cf. 176 → 179).88

Scheme 26. Cycloisomerization strategy for the total synthesis of echinopine B by Vanderwal and co-workers.

The synthesis commences with a three step ring-expansion sequence from cyclohexanone 183 to cycloheptenone 185 (Scheme 27). In the event, the corresponding TMS-enol ether underwent a

Simmons–Smith cyclopropanation followed by FeCl3-mediated ring opening/elimination. Alkyne 186, obtained in seven additional steps, was alkylated, providing cyclization precursor 187. The desired cycloisomerization product 188 was subsequently obtained upon exposure of 187 to catalytic amounts of

PtCl2. Targeted echinopine B (175) could be isolated upon oxidation of the methoxyenol ether with PCC.

Scheme 27. Total synthesis of echinopine B by Vanderwal and co-workers.

2.4.2 Echavarren’s synthesis of (–)-nardoaristolone B In 2011, Liu and co-workers reported the gold(I)-catalyzed oxidative cyclization of 1,5-enynes, enabled by N-oxides.89 As shown in Scheme 28 (top), following metal activation of the alkyne

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses nucleophilic attack of the oxidant generates 191, which leads to gold carbene 192 with concomitant N–O bond rupture. An intramolecular cyclopropanation reaction then leads then to the final product 193.

Scheme 28. Gold(I)-mediated oxidative cyclization of 1,5-enynes by Liu and total synthesis of (–)-nardoaristolone B by Echavarren.

Echavarren and co-workers realized the potential of this methodology to provide a concise route towards the recently isolated90 natural product (–)-nardoaristolone B (198).91 In five steps, cyclohexenone 194 was transformed into enantiopure 1,5-enyne 195. The envisioned gold(I)-catalyzed oxidative enyne cyclization required some optimization. Extensive screening of gold catalysts and N- oxides was necessary in order to achieve a high yielding cycloisomerization. Accordingly, the use of

IPrAuNTf2 in combination with 196 as oxidant, resulted in 74% isolated yield of desired cyclopropane 197. The remaining allylic oxidation to form (–)-nardoaristolone B (198) occurred via a palladium- catalyzed radical oxidation in presence of Pearlman’s catalyst.92

2.4.3 Ferreira’s synthesis of gelsenicine During their total synthesis of the alkaloid gelsenicine (199), Ferreira and co-workers reported an impressive example of a cycloisomerization resulting in the stereoselective formation of a highly substituted cyclopropane (

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Scheme 29).93 This natural product consists of a tricyclic caged core, which is fused to a spirocyclic oxindole. Advanced diene 200 was envisaged as a suitable precursor for gelsenicine (199). Cope reasrrangement would retrosynthetically lead to cyclopropane 201, which in turn would be synthesized via a transition metal-catalyzed cycloisomerization from alkyne 202. Noteworthy, this two-step sequence (202 → 200) might be even realized as one-pot cascade reaction.

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Scheme 29. Ferreira’s retrosynthetic analysis of gelsenicine.

Alkyne 202, prepared in three steps from commercially available starting materials, was exposed to

PtCl2 at 70 °C to induce both, the cycloisomerization and the Cope rearrangement. However, desired bicyclic structure 200 could only be obtained in poor yield of 5%. Hence a two-step sequence was explored next. However, while the cycloisomerization reaction provided 201 in excellent yield, 200 was formed in only minor amounts. This finding could be attributed to competing hydrogen migration from

Scheme 30. Total synthesis of gelsenicine by Ferreira and co-workers.

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses the n-propyl group to the enoate olefin. Thus, diyne 203, which could later also be converted into the required ethyl ketone, was investigated. Indeed, upon exposure to 2 mol% of gold(I)-catalyst 204, cyclopropane 205 could be isolated in 93% yield. Upon heating in methanol, initial isomerization to 206 was followed by Cope rearrangement, providing 207 in 75% yield. Mercury-mediated hydration then installed the crucial ethyl ketone in 208. The two remaining heterocyclizations were tackled in the final phase of the synthesis. The oxindole was formed in 86% yield upon treatment of 209 with PhI(OTFA)2 and the pyrroline was formed under radical conditions, ultimately providing gelsenicine (199).

2.5 Kulinkovich Reaction 2.5.1 Corey’s synthesis of (–)-β-araneosene (–)-β-Araneosene (211) is a metabolite isolated from the terrestrial mold Sordaria araneosa and belongs to a class of natural products characterized by a trans-fused 11/5 ring system (Scheme 31).94 In 2005, Corey and Kingsbury reported an elegant total synthesis of this intriguing natural product, generating the cyclopentane by a pinacol rearrangement.95 Diol 212, which incorporates a quaternary stereocenter, was envisioned to arise from ring expansion of cyclopropanol 213.

As indicated in Scheme 31, exposure of ester 214 to ClTi(Oi-Pr)3 and EtMgBr furnished Kulinkovich product 215 in 60% yield. While catalysis by Brønsted acids resulted in partial decomposition of the material, treatment of 215 with AlMe3 induced the desired ring expansion to give cyclobutanone 216 in remarkable 90% yield. A salient feature of this sequence is the stereochemically controlled installation of the quaternary center. After four additional steps, diol 212 was obtained, which smoothly underwent a pinacol rearrangement in 98% yield upon treatment with MsCl and triethylamine.

Scheme 31. Total synthesis of (–)-β-araneosene by Corey and Kingsbury.

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2.5.2 Cha’s synthesis of cyathins A3 and B2 Most members of the cyathane metabolites contain a 5/6/7-tricyclic skeleton, with a trans-fused 96 cycloheptene. In 2009, Cha and Kim reported the total synthesis of cyathins A3 and B2, in which Prins- type cyclopropane expansion (220 → 219, Scheme 32) was employed to control the generation of the C(5) and C(6) stereocenters.97 As in the Corey synthesis of (–)-β-araneosene (vide supra), the crucial cyclopropanol would arise from the corresponding ester 221 via Kulinkovich reaction. In the event, known ester 221 underwent the cyclopropanation and TMS protection in 51% overall yield. The desired Prins-type ring expansion of 220 occurred in 78% yield upon exposure of the latter to

TiCl4 and acetal 222. The resulting methoxyether, obtained as a mixture of diastereomers, smoothly underwent zinc-mediated dehalogenation to furnish alkene 219 in 85% yield. In nine steps, sulfoxide

224 was obtained, which underwent a Pummerer rearrangement, giving cyathin B2 (218). Furthermore, the latter could also be transformed into cyathin A3, another member of this class of diterpenoids.

Scheme 32. Total synthesis of cyathin B2 by Cha and Kim.

2.5.3 Cha’s synthesis of alkaloid (–)-205B In 1987, Tokuyama investigated the skin extracts of the poisonous frog Dendrobates pumilio and discovered various indolizidine alkaloids.98 Among these, alkaloid (–)-205B (225) gained considerable interest in the synthetic community as a platform to test new methods and strategies AA

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(Scheme 33).99,100,101,102 In their retrosynthetic analysis, Cha and Rao disconnected 225 to allene 226.103 The synthesis of the latter would be achieved by employing methods involving homoenolates developed in their laboratory.104 The required nucleophiles are generated in situ from cyclopropanols and were shown to react with a variety of electrophiles. Upon exposure of ester 229 to standard Kulinkovich conditions, cyclopropanol 230 could be isolated in excellent yield of 92%. In four additional steps, the synthesis of azide 228 was achieved, which underwent homoenolate coupling with tosylate 227 in remarkable 79% yield. Piperidine 226 was formed by intramolecular aza-Wittig reaction upon treatment with triphenylphosphine and subsequent imine reduction. Silver-mediated allene cyclization followed by ring-closing metathesis then provided alkaloid (–)-205B (225).

Scheme 33. Total synthesis of alkaloid (–)-205B by Cha and Rao.

2.6 Other Methods 2.6.1 From 1-Pyrazolines Documented in 1903 by Büchner and Perkel, the thermal decomposition of 1-pyrazolines to generate 105 cyclopropanes under N2 extrusion is a well-established route (Scheme 34). Additionally, Van Auken and Rinehart discovered that this transformation can also be effected by irradiation.106 In the following section, we showcase noteworthy examples in which this transformation is implemented in the synthesis of complex targets.

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Scheme 34. Preparation and decomposition of 1-pyrazolines to cyclopropanes.

2.6.1.1 Echavarren’s synthesis of lundurines A-C During the initial retrosynthetic analysis of lundurines A-C, Echavarren and co-workers envisioned employing a diazo-derived carbene precursor such as 237 to generate the crucial cyclopropane motif (Scheme 35).107 The latter would then be synthesized from alkyne 238 by a gold(I)-mediated hydroarylation.

Indole 239, obtained in two steps from tryptamine, was treated with 5 mol% AuCl3 and underwent hydroarylation to give 240 in 79% yield. While initial attempts to induce the cyclopropanation event by various transition metal processes failed, pyrazoline 242 was formed in the presence of BF3·OEt2. The latter suffered from N2 extrusion in situ, furnishing cyclopropane 243 in remarkable 80% yield. Advanced intermediate 243 could then be transformed into (–)-lundurine A (72) as well as structurally related lundurines B and C.

Scheme 35. Total synthesis of lundurin A by Echavarren and co-workers.

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2.6.1.2 Liang’s synthesis of echinopines A and B Liang’s strategy for the introduction of the cyclopropane in echinopines A and B also relies on a pyrazoline decomposition reaction (Scheme 36).108 Hence, diazo compound 245 was introduced so that it would participate in an intramolecular 1,3-dipolar cycloaddition reaction to establish the tricyclic core of the echinopines. The synthesis commenced with the preparation of ketone 248 by an aldol/Henry sequence, followed by oxidation. The cis-fused 5/7 system was synthesized by Tiffeneau–Demjanov rearrangement (249 → 250). Condensation of ketone 251 with TsNHNH2 and in situ liberation of the corresponding diazo compound delivered upon heating pyrazoline 244 in 68% yield. Subsequent irradiation mediated the desired decomposition to provide cyclopropane 252 in 66% yield, from which echinopines A and B could be accessed in four, and five steps respectively.

Scheme 36. Total synthesis of echinopine B by Liang and co-workers.

2.6.2 Cycloadditions 2.6.2.1 Mulzer’s synthesis of (–)-penifulvin A In 1985 in pioneering studies, Wender and Ternansky investigated the irradiation of arene olefins.109 When compound 253 was exposed to UV light, highly congested tetracyclic systems 255 and 256 were isolated in 70% yield as a 1:1 mixture (Scheme 37, top). This remarkable transformation was then brilliantly used to enable the synthesis of (+)-silphinene. Gaich and Mulzer exploited this cycloaddition reaction in a remarkably efficient nine-step synthesis of (–)-penifulvin A (263), a sesquiterpenoid isolated from the fungus Pennicillium griseofulvum.110,111 Irradiation of arene 258, available as enantioenriched material in three steps from 257, provided a 1:1 mixture of cyclopropanes 259 and 260 in a combined yield of 70%. Reductive cyclopropane opening of the latter then gave alcohol 261, which was oxidized to the corresponding carboxylic acid in excellent

Carreira OC V Fall 2018 Document on Cyclopropanations in Syntheses yield. Ozonolysis of the cyclopentene was followed by PDC-mediated lactol oxidation to furnish (–)- penifulvin A (263) in 64% yield.

Scheme 37. Photoinduced cycloaddition of arene olefins and total synthesis of (–)-penifulvin A by Mulzer and Gaich.

2.6.2.2 Shi’s synthesis of neofinaconitine

The norditerpenoid alkaloid neofinaconitine (264) was isolated in 1988 (

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Scheme 38).112 Surprisingly, the first total synthesis was only reported in 2013 by Shi.113 In order to provide rapid entry to the pentacyclic skeleton of the natural product, an intramolecular radical addition with concomitant cyclopropane fragmentation (265 → 264) was envisioned. This cyclopropane would be installed by an unusual Diels–Alder reaction involving cyclopentadiene 267 and cyclopropene 268.114 Several possible issues needed to be taken into account while planning this transformation. Firstly, regioselective approach of the dienophile to the cyclopentadiene is required. Secondly, cyclopropenes are highly reactive intermediates, which are ideally prepared in situ or immediately consumed. Thirdly, substituted cyclopentadienes are known to undergo thermally allowed 1,5-hydrogen shifts, an event which entails the formation of regioisomeric cycloadducts.

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Scheme 38. Retrosynthetic analysis of neofinaconitine by Shi et al.

In initial studies, attempts were made to isolate 267 and allow it to react with cyclopropene 268; however, only intractable mixtures of cyclopentadiene dimers were obtained. Thus, Shi subsequently prepared the cyclopentadiene under standard conditions (TBSOTf, NEt3) and directly introduced cyclopropene 268 to the reaction mixture. The targeted cycloadduct 266 was isolated as the major component of an isomeric mixture. After four additional synthetic steps, Weinreb amide 270 could be accessed in 42% yield from cyclopentenone 269. As a first generation synthesis, including direct cyclopropane fragmentation failed, a new strategy was devised. Accordingly, TBAF-mediated desilylation was followed by acid-catalyzed fragmentation, which cleaved the internal cyclopropyl C–C bond to give bromide 271 in 62% overall yield. The latter was then converted into bromide 272, which underwent a highly efficient radical 1,4-conjugate addition to ketone 273 upon exposure to n-

Bu3SnH/AIBN.

Scheme 39. Total synthesis of neofinaconitine by Shi et al.

2.6.3 Iodonium Ylides 2.6.3.1 Carreira’s synthesis of (+)-crotogoudin The diterpene (+)-crotogoudin (274), isolated in 2010 from Croton plants, possesses a unique tetracyclic skeleton, incorporating two quaternary stereocenters, which flank a hindered tertiary oxygen functionality (Scheme 40).115 In 2013, Carreira and Breitler reported an annulative cascade commencing from cyclopropane 275 to generate the central cyclohexane ring.116 The propensity of cyclopropanes substituted with acceptor groups to participate in either radical or ionic transformations was exploited. Chemoselective cyclopropanation of the 1,1-disubstituted olefin in 276 would generate 275. Accordingly, ketone 277 underwent selective nucleophilic addition upon exposure to GG

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isopropenylmagnesium bromide and LaCl3·2LiCl. Subsequent protection of the secondary alcohol provided olefin 279 in 86% yield. Phenyliodonium malonate 280 was chosen as a suitable carbenoid precursor as a consequence of the reported selectivity for 1,1-disubstituted olefins.117 Thus, exposure of the latter to olefin 279 in the presence of 0.1 mol% Rh2(esp)2 furnished cyclopropylmalonate 281 in 66% yield and 4.4:1 d.r. In three steps, lactone 282 was obtained. While initial approaches, in which the cyclopropane would be used as a homo-Michael acceptor in the course of nucleophilic attack by the trisubstituted olefin were not productive, SmI2-mediated a radical annulation, providing desired 283 in 80% yield. Targeted (+)-crotogoudin (274) could then be accessed in seven more steps.

Scheme 40. Total synthesis of (+)-crotogoudin by Carreira and Breitler.

2.6.4 Reductive Cyclopropanation 2.6.4.1 Baran’s synthesis of steviol In 2013, Baran and co-workers reported the total synthesis of the ent-kaurane steviol (284, Scheme 41).118 At the heart of their strategy is fragmentation of highly substituted cyclopropane 285, which was envisoned to be accessible from diketone 286 by reductive cyclopropanation. Enone 287, obtained by polyene cyclization and reduction, underwent a photo [2+2] cycloaddition with allene in 82% yield. The methylene cyclobutane obtained was transformed into the corresponding diketone via ozonolysis. Subsequent fragmentation under acidic conditions generated diketone 289 in 62% yield. Reductive cyclopropanation with zinc and HCl in acetic anhydride afforded key cyclopropane intermediate 290. After extensive screening of fragmentation conditions, it was found that treatment of diacetate 290 with methanolic HCl at 0-6 °C gave cyclopentanone 291 in 79% yield, from which steviol (284) could be accessed in three additional steps. HH

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Scheme 41. Total synthesis of steviol by Baran and co-workers.

Abbreviations

°C degree Celsius Ac acetyl AIBN azobisisobutyronitrile Ar aryl BHT 2,6-di-tert-butyl-4-methylphenol Bn benzyl Boc tert-butoxycarbonyl Bu butyl Bz benzoyl cal calorie cap caprolactam cf. confer Cp cyclopentadienyl Cp* pentamethylcyclopentadienyl dba dibenzylideneacetone DIBAL diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMP Dess–Martin periodinane DMS dimethyl sulfide DMSO dimethylsulfoxide E electrophile esp α,α,α’,α’-tetramethyl-1,3-benzenedipropionate

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Et ethyl EWG electron withdrawing group hfacac hexafluoroacetylacetonato IBX 2-iodoxybenzoic acid imid imidazole IPr N,N’-bis(2,6-diisopropylphenyl)-imidazol-2-ylidiene LDA lithium diisopropylamide Me methyl MOM methoxymethyl acetal Ms methanesulfonyl MTM methylthiomethyl PCC pyridinium chlorochromate PDC pyridinium dichromate pfb perfluorobutyrate Ph phenyl Piv pivaloyl PMB para-methoxybenzyl PPA polyphosphoric acid Pr propyl py pyridine RT room temperature TBAF tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl TES triethylsilyl Tf trifluoromethanesulfonate TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TIPS triisopropylsilyl TMP 2,2,6,6-tetramethylpiperidine TMS trimethylsilyl TMTU tetramethylthiourea Ts para-toluenesulfonyl UV ultraviolet

1 This document is a condensed version of a review that appeared in Chem. Rev.(ACS) by Carreira and Ebner and is generated for educational purposes. You are advised to read the full review by consulting: Chem. Rev., 2017, 117 (18), pp 11651–11679 2 a) Simmons, H. E.; Smith, R. D.; J. Am. Chem. Soc. 1958, 80, 5323-5324; b) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256-4264. 3 Stereospecificity: „A reaction is termed stereospecific if starting materials differing only in their configuration are converted into stereoisomeric products. According to this definition, a stereospecific process is necessarily stereoselective but not all stereoselective processes are stereospecific.

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Stereospecificity may be total (100%) or partial. The term is also applied to situations where reaction can be performed with only one stereoisomer. For example, the exclusive formation of trans-1,2- dibromocyclohexane upon bromination of cyclohexene is a stereospecific process, although the analogous reaction with (E)-cyclohexene has not been performed.” Original quote from the IUPAC goldbook (PAC 1994, 66, 1077). 4 a) Winstein, S.; Sonnenberg, J.; Devries, L. J. Am. Chem. Soc. 1959, 81, 6523-6524; b) Winstein, S.; Sonnenberg, J. J. Am. Chem. Soc. 1961, 83, 3235-3244; c) Dauben, W. G.; Berezin, G. H. J. Am. Chem. Soc. 1963, 85, 468-472; d) Dauben, W. G.; Ashcraft, A. C. J. Am. Chem. Soc. 1963, 85, 3673- 3676; e) Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc. 1969, 91, 6892-6894. 5 a) Wittig, G.; Schwarzenbach, K. Angew. Chem. 1959, 71, 652; b) Wittig, G.; Schwarzenbach, K. Liebigs Ann. Chem. 1962, 650, 1-20; c) Wittig, G.; Wingler, F. Justus Liebigs Ann. Chem. 1962, 656, 18-21; d) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2146-2164; e) Wittig, G.; Jautelat, M. Liebigs Ann. Chem. 1967, 702, 24-37. 6 a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron. Lett. 1966, 7, 3353-3354; b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron. 1968, 24, 53-58. 7 Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974-6981. 8 a) Yang, Z. Q.; Lorenz, J. C.; Shi, Y. Tetrahedron. Lett. 1998, 39, 8621-8624; b) Lorenz, J. C.; Long, J.; Yang, Z. Q.; Xue, S.; Xie, Y.; Shi, Y. J. Org. Chem. 2004, 69, 327-334; see also: Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am. Chem. Soc. 2001, 123, 8139-8140. 9 a) Lacasse, M. C.; Poulard, C.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 12440-12441; b) Voituriez, A.; Zimmer, L. E.; Charette, A. B. J. Org. Chem. 2010, 75, 1244-1250. 10 Original quote from: Silberrad, O.; Roy, C. S. J. Chem. Soc. 1906, 89, 179-182. 11 a) Nozaki, H.; Moriuti, S.; Yamabe, M.; Noyori, R. Tetrahedron Lett. 1966, 59-63; b) Moser, W. R. J. Am. Chem. Soc. 1969, 91, 1141-1146. 12 a) Paulissen, R.; Teyssie, P.; Hubert, A. J. Tetrahedron. Lett. 1972, 1465-1466; b) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron. Lett. 1973, 2233-2236; c) Hubert, A. J.; Noels, A. F.; Anciaux, A. J. ; Teyssié, P. Synthesis 1976, 600-602. 13 a) Maas, G. Angew. Chem. Int. Ed. 2009, 48, 8186-8195; b) Morandi, B.; Dolva, A.; Carreira, E. M. Org. Lett. 2012, 14, 2162-2163; c) Morandi, B.; Carreira, E. M. Science 2012, 335, 1471-1474; d) Künzi, S. A.; Morandi, B.; Carreira, E. M. Org. Lett. 2012, 14, 1900-1901; e) Morandi, B.; Cheang, J.; Carreira, E. M. Org. Lett. 2011, 13, 3080-3081; f) Morandi, B.; Mariampillai, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2011, 50, 1101-1104. 14 Wulfman, D. S.; Linstrumelle, G.; Cooper, C. F. In The Chemistry of Diazonium and Diazo Groups; Patai, S., Ed.: Wiley: New York, 1978. 15 Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N. J. Am. Chem. Soc. 1992, 114, 1874-1876. 16 For selected reviews, see: a) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385-5453; b) Ye, T.; Mckervey, M. A. Chem. Rev. 1994, 94, 1091-1160; c) Honma, M.; Takeda, H.; Takano, M.; Nakada, M. Synlett 2009, 1695-1712; d) Reisman, S. E.; Nani, R. R.; Levin, S. Synlett 2011, 2437-2442; e) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911-935; e) Doyle, M. P. J. Org. Chem. 2006, 71, 9253-9260. 17 Geuther, A. Ann. 1862, 123, 121-122. 18 Doering, W. V.; Hoffmann, A. K. J. Am. Chem. Soc. 1954, 76, 6162-6165. KK

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